What causes factor XIII (FXIII) deficiency?

Updated: Apr 02, 2018
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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Answer

To date, most identified mutations leading to severe FXIII deficiency and a bleeding disorder involve subunit A, with very few mutations reported involving subunit B. The gene for subunit A is located on chromosome 6 bands p24-25. The gene is 160 kilobases in length and has 15 exons and 14 introns with specific structural and functional domains. Catalytic activity is encoded in the second exon, and the active cysteine is encoded by the seventh exon. The 2 Ca2+ -binding sites and a thrombin-inactivation site have been identified at other locations. The gene for subunit B is located on chromosome 1 bands q31-32.1, is 28 kilobases in length, and has 12 exons and 11 introns. [10, 74] (See the image below.)

Gene, messenger RNA, and protein for subunit A of Gene, messenger RNA, and protein for subunit A of factor XIII. Adapted from Reitsma PH. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins; 2001:59-87 and from Roberts HR, Monroe DM III, Hoffman M. In: Williams Hematology. McGraw-Hill Professional; 2001:1409-34.

Detailed characteristics of complementary ribonucleic acid (cRNA) and messenger ribonucleic acid (mRNA) of the placental subunit A are known. The presence of an acetylated amino terminal end and the absence of glycosylation and disulfide bonds apparently are features typical of secreted cytoplasmic proteins. The presence of these characteristics makes it conducive for subunit A expressed in yeast systems to make a recombinant product.

Substitutions in the core domain of the enzyme, affecting highly conserved residues, result in a serious defect in structure and function. Missense mutations in the A chain are a common cause, accounting for approximately 50% of cases of severe FXIII deficiency. The defects result in an absence of subunit A protein but also are accompanied by a reduction in subunit B carrier protein (type II defect).

Nonsense mutations are an equally common cause of A chain defects, resulting in a frameshift-type, splice-type, or termination-type mutation. The few defects that have been reported in the B chain lead to a deficiency of the carrier protein (subunit B), which then leads to instability and reduction of plasma subunit A levels despite the presence of functional intracellular subunit A (type I defect). [75] Therefore, patients who are homozygous for subunit B mutations have a bleeding disorder. Most recently, impaired intracellular transport from the endoplasmic reticulum to the Golgi apparatus, with failure of secretion of the truncated FXIII subunit B produced by a single-base deletion, was reported to be the cause of severe FXIII deficiency in 3 unrelated patients. [76]

Many kinds of mutations have been (and continue to be) identified, with some mutations unique to certain families. The finding of compound heterozygotes has eliminated the mandatory search for consanguinity in all parents of patients with severe FXIII deficiency. [77, 78, 45]

An unusual mutation has been described in 2 Finnish sisters with a very mild bleeding disorder. One sister had 2 successful pregnancies without regular replacement therapy. The sisters had no detectable subunit A activity (<1%) using plasma screening tests; however, using the 3H-putrescine incorporation assay, subunit A showed 0.35% of normal activity, with partial g-g dimerization of fibrin in clotted plasma. A full-length subunit A was detected in the patients' platelets using Western blot analysis.

The sisters had an Arg661→stop mutation on one allele and a T→C transition on the other allele. These data showed that a mutation in the splice donor site of intron C can result in different variant mRNA transcripts and that small amounts of correctly processed mRNA can produce a type of FXIII that can produce, at least, dimerization of fibrin, thus minimizing the clinical consequences. [73]

Various reported mutations are spread throughout the gene coding for FXIII without specific hot spots. In many patients, low steady-state mRNA levels have been found, which result in inefficient production of the abnormal protein. [11]


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